Systems and methods for treating a mucosal surface

ABSTRACT

A system for treating a condition associated with a mucosal surface, the system comprising an immune response modifier (IRM) compound chosen from imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, 1,2-bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof and an applicator device for applying the IRM compound to the mucosal surface. This system of IRM compounds and applicator may be used to treat conditions associated with mucosal surfaces such as cervical dysphasia and cervical intraepithelial neoplasia.

[0001] This application is a continuation-in-part (CIP) of co-pendingapplication Ser. No. 09/676,339 filed Sep. 29, 2000, which is acontinuation of application Ser. No. 09/479,578 filed Jan. 7, 2000 (nowU.S. Pat. No. 6,245,776), which claimed priority to application No.60/115,253 filed Jan. 8, 1999. This application also claims the benefitof priority of the provisional application No. 60/213,420 filed Jun. 22,2000. In addition, the disclosure of each of the above mentionedapplications is incorporated herein by reference.

DESCRIPTION OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to systems and methods for treatinga condition associated with a mucosal surface, such as the vaginal partof the cervix. In particular, the systems and methods may involve animmune response modifier (IRM) compound chosen from imidazoquinolineamines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridineamines, imidazonaphthyridine amines, oxazoloquinoline amines,thiazoloquinoline amines, 1,2-bridged imidazoquinoline amines, andpharmaceutically acceptable salts thereof. In one optional embodiment,the invention provides systems and methods which are particularlyadvantageous for topical application to the cervix for treatment ofcervical conditions such as cervical dysplasias including dysplasiaassociated with human papillomavirus (HPV).

[0004] The present invention is also directed to medicament deliveryarrangements and methods of use. Some aspects of the invention aredirected to the delivery of a pharmacological agent to a selectedlocation with minimal delivery to regions surrounding the selectedlocation. In some optional embodiments the invention is particularlyadvantageous for topical delivery of a pharmacological agent to theuterine cervix.

[0005] 2. Background of the Invention

[0006] Many imidazoquinoline amine, imidazopyridine amine, 6,7-fusedcycloalkylimidazopyridine amine, 1,2-bridged imidazoquinoline amine,thiazolo- and oxazolo-quinolinamines and pyridinamines,imidazonaphthyridine and tetrahydroimidazonaphthyridine amine compoundshave demonstrated potent immunostimulating, antiviral and antitumor(including anticancer) activity, and have also been shown to be usefulas vaccine adjuvants to enhance the protective immune system response tovaccines. These compounds are hereinafter sometimes collectivelyreferred to as the “IRM” (immune response modifier) compounds of theinvention. An IRM compound may be selected from the group comprisingimidazoquinoline amines, imidazopyridine amines, 6,7-fusedcycloalkylimidazopyridine amines, imidazonaphthyridine amines,oxazoloquinoline amines, thiazoloquinoline amines 1,2-bridgedimidazoquinoline amines, and pharmaceutically acceptable salts thereof.Methods for preparing such IRMs and pharmaceutical compositionscontaining them are disclosed in, for example, U.S. Pat. Nos. 4,689,338;5,389,640; 5,268,376; 4,929,624; 5,266,575; 5,352,784; 5,494,916;5,482,936; 5,346,905; 5,395,937; 5,238,944; 5,525,612; 5,175,296;5,693,811; 5,741,908; 5,939,090; 6,110,929; 4,988,815; 5,376,076; andPCT Publications WO 99/29693; WO 00/76505; WO 00/76518; and WO 00/76519.The entire disclosure of each of these patents and patent applicationsis incorporated herein by reference.

[0007] The immunostimulating, antiviral and antitumor activities ofthese compounds have been discussed in detail, and certain specificdiseases have been identified as being susceptible to treatmenttherewith, including basal cell carcinoma, eczema, essentialthrombocythaemia, hepatitis B, multiple sclerosis, neoplastic diseases,psoriasis, rheumatoid arthritis, type I herpes simplex, type II herpessimplex, and warts. One of these IRM compounds, known as imiquimod, hasbeen commercialized in a topical formulation, Aldara™, for the treatmentof anogenital warts associated with human papillomavirus.

[0008] The mechanism for the antiviral and antitumor activity of theseIRM compounds is thought to be due in substantial part to enhancement ofthe immune response due to induction of various important cytokines(e.g., interferons, interleukins, tumor necrosis factor, etc.). Suchcompounds have been shown to stimulate a rapid release of certainmonocyte/macrophage-derived cytokines and are also capable ofstimulating B cells to secrete antibodies which play an important rolein these IRM compounds' antiviral and antitumor activities. One of thepredominant immunostimulating responses to these compounds is theinduction of interferon (IFN)-α production, which is believed to be veryimportant in the acute antiviral and antitumor activities seen.Moreover, up regulation of cytokines such as, for example, tumornecrosis factor (TNF), IL-1 and IL-6 also have potentially beneficialactivities and are believed to contribute to the antiviral and antitumorproperties of these compounds.

[0009] Although some of the beneficial effects of IRMs are known, theability to provide therapeutic benefit via topical application of an IRMfor treatment of a particular condition at a particular location may behindered due to tissue irritation, formulation wash away, poorpermeation or undesired systemic delivery of the topically appliedcompound. Accordingly, there is a need for new methods, formulations,and systems to provide the greatest therapeutic benefit from this classof compounds.

[0010] Topical administration of a pharmacological agent to a tissuesurface can provide localized therapeutic benefit without concomitantsystemic effects. However, topical application is often difficult orimpossible due to the anatomical location of the tissue. In some cases,application of the agent to a general anatomical region that includes orsurrounds the target tissue may be an alternative to direct topicalapplication. But, if the agent has irritating properties, thisalternative disadvantageously carries with it the possibility ofirritating tissues surrounding the target tissue. In addition, even ifthe agent is non-irritating, regional application typically requires useof a greater volume or concentration of the agent to achieve atherapeutic result equivalent to that achieved by direct application tothe target tissue.

[0011] The uterine cervix is one example of a target tissue to which itis difficult to apply a topical agent. Relative to a standing position,the cervix is typically located at the uppermost portion of the vaginalcavity. However, while the cervix is located at the uppermost portion ofthe vaginal cavity, age, the stage of the estrous cycle, pregnancy, andother factors cause variability of the location of the cervix betweendifferent women and in the same woman at different stages of life.

[0012] Certain cervical conditions can be advantageously treated bytopical administration of a pharmacological agent. Cervical dysplasia isan example of a pathological condition that can be effectively treatedby direct delivery of medication to the surface of the cervix where theabnormal cells are typically found. Unfortunately, most currentlyavailable applicators for vaginal drug delivery are inadequate forapplying a medication to the surface of the cervix. And, since cervicaldysplasia can lead to cervical cancer, an applicator that is less thanoptimal is not an acceptable option.

[0013] Most presently available vaginal applicators are for applicationto the vaginal cavity generally and not for direct application to thecervix. In general, the length and configuration of the applicators areinsufficient to ensure delivery of an agent to the uppermost portion ofthe vaginal cavity. Delivery to the middle or lower portion of thevagina does not ensure that an agent will reach the cervical tissue inthe upper portion of the vagina. In addition, with the exception ofcertain body orientations, gravity tends to drain agents away from thecervix. Normal discharge and flow of fluids, both menstrual andnon-menstrual, also drain away from the cervix. Thus, any applicatorthat is not capable of repeatedly delivering an appropriate amount ofagent to the uppermost end of the vaginal cavity risks less than optimaltreatment.

[0014] Overcoming the inaccuracy of present vaginal applicators, whenused for cervical delivery of an agent, by delivering an excess volumeor concentration of the medication may be unacceptable due to the riskof undesired effects to surrounding tissues. However, delivery ofreduced volumes or concentrations to avoid irritation to surroundingtissue risks the serious consequences of ineffective treatment.

[0015] Accordingly, there is continuing need for improved deliverysystems and methods for topical application of a pharmacological agent.

SUMMARY OF THE INVENTION

[0016] One aspect of the invention includes a system for treating acondition associated with a mucosal surface. The system comprises animmune response modifier (IRM) compound chosen from imidazoquinolineamines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridineamines, 1,2-bridged imidazoquinoline amines, and pharmaceuticallyacceptable salts thereof. The system also comprises an applicator devicefor applying the IRM compound to the mucosal surface.

[0017] Another aspect of the invention includes a system comprising animmune response modifier (IRM) compound chosen from imidazoquinolineamines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridineamines, imidazonaphthyridine amines, oxazoloquinoline amines,thiazoloquinoline amines, 1,2-bridged imidazoquinoline amines, andpharmaceutically acceptable salts thereof. The system also includes anapplicator device for applying to the mucosal surface the IRM compound.

[0018] For example, the IRM compound may be1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine, or4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanolor 2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine.

[0019] The system may be used for treating a condition associated withthe mucosal surface on a cervix, optionally, the vaginal part of thecervix. Exemplary conditions associated with the mucosal surface includecervical dysphasia and cervical intraepithelial neoplasia.

[0020] In an exemplary embodiment, the applicator device may comprise ahollow tube and a piston slidably received within the tube.

[0021] Yet another aspect of the invention includes a method fortreating a condition associated with a mucosal surface. The methodcomprises providing an immune response modifier (IRM) chosen fromimidazoquinoline amines, imidazopyridine amines, 6,7-fusedcycloalkylimidazopyridine amines, imidazonaphthyridine amines,oxazoloquinoline amines, thiazoloquinolines amines, 1,2-bridgedimidazoquinoline amines, and pharmaceutically acceptable salts thereof.The method also includes providing an applicator device for applying tothe mucosal surface the IRM compound. In addition, the method furtherincludes applying the IRM compound to the mucosal surface with anapplicator device.

[0022] The method may involve inserting the applicator device into thevagina, positioning a distal end of the applicator device adjacent tothe vaginal part of the cervix, and applying the IRM compound to thevaginal part of the cervix.

[0023] At least some of the embodiments disclosed herein providemedicament application systems and methods suitable for topicaladministration of an agent to a target tissue. The systems and methodscould be advantageous for intravaginal delivery of a pharmacologicalformulation. For example, some embodiments provide effective topicalapplication of a pharmacological agent to the cervix for treatment orprevention of conditions including, for example, cervical dysplasia.

[0024] Additional aspects will be set forth in part in the descriptionwhich follows, and in part will be obvious from the description, or maybe learned by practice of the invention. It will be appreciated that atseveral locations throughout the specification, guidance is providedthrough lists of examples. In each instance, the recited list servesonly as a representative group; it is not meant that the list isexclusive.

[0025] It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive.

[0026] The accompanying drawings, which are incorporated in andconstitute a part of this specification, illustrate several embodimentsof the invention and together with the description, serve to explain theprinciples of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027]FIG. 1A is a top view of a treatment system including anapplicator device and a container containing an IRM compound packagedtogether;

[0028]FIG. 1B is a top view of a treatment system with severalpre-filled cartridges of the IRM compound;

[0029]FIG. 2 is an exploded perspective view of components of aintravaginal delivery device;

[0030]FIG. 3 is a proximal end-on view of an exemplary intravaginaldelivery device;

[0031]FIG. 4 is a longitudinal cross-section view of an exemplaryintravaginal delivery device taken through line 4-4 with the pushingmember retracted proximally;

[0032]FIG. 5 is a longitudinal cross-section of an exemplaryintravaginal delivery device with the pushing member advanced distally;

[0033]FIG. 6 is a close-up view of the proximal end of the intravaginaldelivery device illustrated in FIG. 5;

[0034]FIG. 7 is a close-up view of the distal end of the intravaginaldelivery device illustrated in FIG. 5;

[0035]FIG. 8 is an exploded perspective view of components of anoptional alternative embodiment of an intravaginal delivery deviceaccording to the invention;

[0036]FIG. 9 is a longitudinal cross-section view of the intravaginaldelivery device of FIG. 8 with the pushing member retracted proximally;

[0037]FIG. 10 is a longitudinal cross-section view of the intravaginaldelivery device of FIG. 8 with the pushing member distally advanced;

[0038]FIG. 11 is a close-up view of the distal end of the intravaginaldelivery device illustrated in FIG. 10;

[0039]FIG. 12 is a close-up view of the proximal end of the drugdelivery device of FIG. 10;

[0040]FIG. 13 is a perspective view of an alternative proximal end foran intravaginal delivery device;

[0041]FIG. 14 is a perspective view of another alternative proximal endfor an intravaginal delivery device;

[0042]FIG. 15 is a longitudinal cross section view of an exemplaryintravaginal delivery device pre-filled with a formulation;

[0043]FIG. 16 is a graph comparing imiquimod transport across hairlessmouse skin from three pharmaceutical formulations each containing 5%imiquimod;

[0044]FIG. 17 is a graph comparing imiquimod transport across hairlessmouse skin from four pharmaceutical formulations containing variedconcentrations of imiquimod and isostearic acid;

[0045]FIG. 18 is a graph comparing mean serum imiquimod concentration inrats after a single intravaginal dose of Formulation A or Formulation B;and

[0046]FIGS. 19A and 19B provide bar graphs of the pharmacokineticcomparison of imiquimod in rats after vaginal dosing of Formulation A orFormulation B.

DESCRIPTION OF THE EMBODIMENTS

[0047] Reference will now be made in detail to some exemplaryembodiments of the invention, examples of which are illustrated in theaccompanying drawings. Wherever possible, the same reference numberswill be used throughout the drawings to refer to the same or like parts.

[0048] The present invention may be, in part, directed to medicamentapplicators and methods for delivery of a pharmacological agent to aselected location. In some optional embodiments, the dispensers may beparticularly suited for intravaginal delivery of a pharmacologicalagent. In optional embodiments, the disclosed dispensers may provide fortopical application of the pharmacological agent to an intravaginallocation, such as the cervix, for treatment of conditions including, forexample, cervical dysplasia. In general, the dispensers may be used todeliver a pharmacological agent in a frequency and amount necessary toobtain a desired treatment result.

[0049] Throughout the specification, guidance may be provided throughlists of examples. In each instance, the recited list serves only as arepresentative group. It is not meant, however, that the list isexclusive.

[0050] As used herein the term “pharmacological agent” includes anyagent or combination of agents that can be used to diagnose, treat,cure, ameliorate, prevent or otherwise manage a condition of a patient.The term “condition” refers to any infectious, non-infectious,pathological, physiological, biochemical or other state of a patient'sbody that can be treated according to the invention.

[0051] Throughout the specification, unless otherwise stated, the terms“proximal” and “distal” are relative terms. The term “proximal” refersto a location nearest the user (for example, the user's hand that isoperating the dispenser) and the term “distal” refers to a locationfarthest from the user. Thus, in a typical embodiment, the proximal endof the delivery device will be nearest to or grasped by the hand of theuser and the distal end of the instrument will be located nearest to thetissue site at which the agent will be applied.

[0052] As used herein, a “mucosal associated condition” means aninflammatory, infectious, neoplastic or other condition that involves amucosal surface or that is in sufficient proximity to a mucosal surfaceto be affected by a therapeutic or prophylactic agent topically appliedto the mucosal surface.

[0053] Unless stated otherwise, the term “treat”, and derivatives suchas “treatment”, “treating”, etc., are used herein generically toindicate administration of a pharmacological agent for any reason to apatient and is not intended to distinguish a preventative, therapeutic,diagnostic, palliative or other procedure. The term “therapeuticallyeffective amount” means the amount of an agent administered to provide adesired therapeutic effect, such as cytokine induction, antiviral orantitumor activity. A “therapeutically effective amount” includes asingle dose of an agent used in a course of therapy over a period oftime to achieve a desired therapeutic effect.

[0054] Some optional embodiments of devices and methods of the inventionmay be advantageous for delivering an agent to the uterine cervixthrough the vagina to treat (i.e., prevent, diagnose, ameliorate, etc.)a cervical condition. In certain optional embodiments, the dispensers ofthe invention may be particularly advantageous for delivering an immuneresponse modifier (IRM) to the cervix for a cervical condition. Examplesof immune response modifiers suitable for the invention include thosedisclosed in, for example, U.S. Pat. Nos. 4,689,338; 5,389,640;5,268,376; 4,929,624; 5,266,575; 5,352,784; 5,494,916; 5,482,936;5,346,905; 5,395,937; 5,238,944; 5,525,612; 5,175,296; 5,693,811;5,741,908; 5,939,090; 6,110,929; 4,988,815; 5,376,076; and PCTPublications WO 99/29693; WO 00/76505; WO 00/76518; and WO 00/76519. Theentire disclosure of each of these patents and patent applications isincorporated herein by reference. Some optional IRMs suitable for theinvention include 1-(2-methylpropyl)-1H-imidazo[4,5-c] quinolin-4-amine(imiquimod) and compounds and formulations such as disclosed inco-pending U.S. Ser. No. 09/479,578 and PCT Publication WO 00/06577. Theentire disclosure of each of these patents and applications areincorporated herein by reference.

[0055] In general, the “user” of the disclosed dispensers (also referredto herein as applicators) include health care providers who apply theagent to a patient or the patient themselves for self-administration ofthe agent.

[0056] In some optional embodiments, the dispensers can provide foraccurate delivery of a predetermined amount of the pharmacological agentto a selected location with reduced likelihood of inadvertent deliveryto surrounding tissues. Typically, a predetermined amount is atherapeutically effective amount for a single dose. Accurate applicationof the agent to a selected location can advantageously reduce the amountof the agent necessary to achieve a therapeutic result while minimizingthe possibility of irritation to tissues adjacent to the selected siteof application.

[0057] In the case of intravaginal applications, the dispenser mayreduce undesired side effects caused by an agent. For example, whendelivery of an agent is desired only to the cervix, such as for acervical condition, delivery of the agent to locations other than theupper portion of the vaginal cavity can unnecessarily expose the lowervaginal cavity and other surrounding tissues to the agent. This not onlyexposes non-targeted tissues to the agent, but also to potential tissueirritation that can be caused by the agent or other components in apharmacological formulation.

[0058] The intravaginal dispensers may optionally provide for accuratedelivery of a volume of an agent (or formulation thereof) that issmaller than volumes typically used for administering other intravaginalmedications. In some optional embodiments, the intravaginal dispensersmay provide for delivery of about 0.01-10 ml, in other optionalembodiments about 0.5 to 4 ml and typically about 1.0 ml.

[0059] The dispensers can be pre-filled with a therapeutically effectiveamount of a particular agent or filled by the user at the time ofadministration. In the latter situation, the dispensers can beconfigured to receive the agent from a source of the agent (e.g.,aluminum tube, plastic tube, etc.) that can mount to the dispenser forfilling. Some optional dispensers may typically provide for a fixedmaximum volume of the agent. Alternatively, or additionally, thedispensers can have incremental markings for filling with amounts lessthan the maximum volume of the dispenser.

[0060] In an optional embodiment, a pre-filled dispenser may be providedto eliminate the possibility of filling the delivery device with anincorrect amount of the agent. In one optional embodiment, thedispensers may be pre-filled with a formulation including an amount ofimmune response modifier (IRM) compound for a single treatment. Thedispenser, whether pre-filled or not, may be packaged in an outer wrap,such as a foil wrap, which maintains sterility and can act as a moisturebarrier.

[0061] The dispenser may be formed through known methods includinginjection molding processes that form a plastic applicator from polymermaterials such as high density polyethylene, low density polyethylene,linear low density polyethylene, or polypropylene.

[0062]FIG. 1A shows a treatment system 400 including an applicatordevice 10 and a container 401 of a formulation packaged together inpackaging 402. The device 10 could be configured to be filled withformulation contained in the container 401 by placing them in flowcommunication with one another.

[0063]FIG. 1B shows a treatment system 400 where the formulation is acontained in pre-filled cartridges 401 a-401 d capable of being loadedin the dispensing device 10 one at a time.

[0064]FIGS. 2 and 4 show an optional embodiment of an intravaginaldelivery device 10 according to the invention. As illustrated, device 10may include a distal end 1, a proximal end 2 and a longitudinal axis X-Xpassing therethrough. FIG. 2 is an exploded perspective view ofcomponents of device 10 including elongate tube 3 having a delivery end4, an operating end 5 and a lumen 6 passing therethrough. Operating end5 can include handle arrangement 7 such as opposing flanges 8 a and 8 bfor holding device 10 during use. In some embodiments, elongate tube 3may have a length dimension of about 6 cm to about 24 cm, typically,about 10 cm to about 18 cm.

[0065] Pushing member 11 may be slidably received within lumen 6 ofelongate tube 3 and may include a pushing end 12 and a driving end 13.Pushing end 12 may include a platform 14 for placement of a user's thumbor finger to distally advance pushing member 11 within lumen 6. Piston15 may be mountable to driving end 13 of pushing member 11 and may havea distal tip 16 opposite end 17. A cap 18 may be removably mounted tothe distal end 4 of device 10 using known arrangements such as threadsor friction fit, for example.

[0066]FIG. 3 is a distal end view of device 10 and FIG. 4 is alongitudinal cross-section of device 10 taken through line 4-4 of FIG.3. In FIG. 4, piston 15 is shown mounted to the driving end 13 ofpushing member 11 and located at a first position that provides achamber 20 for containing or receiving a predetermined amount of apharmacological agent.

[0067] In some optional embodiments, chamber 20 will provide for avolume of a pharmacological agent of about 5 ml to 0.1 ml, typicallyabout 2 ml to 0.5 ml and optionally about 1.0 ml. In an optionalembodiment, the driving end 13 of pushing member 11 may be removablynested into bore 19 of piston 15. Thus, in this optional embodiment, ifpushing member 11 is retracted proximally the driving end 13 of pushingmember 11 may pull free from bore 19 and piston 15 will not be retractedproximally with pushing member 11. This optional aspect may preventaspiration of an agent after expulsion of the agent from chamber 20 andmay also prevent aspiration of tissue into the delivery end 4 of tube 3if pushing member 11 is retracted proximally.

[0068] In addition, in some optional embodiments, lumen 6 may include astop 40, such as protuberance 41 which may protrude into lumen 6 toprevent proximal retraction of piston 15. Whether device 10 ispre-filled with an agent or filled by the user at the time of use, theposition of stop 40 may provide a fixed maximum volume of chamber 20 tocontain a predetermined amount of an agent. This stop can advantageouslyprevent a user from exceeding a particular dose of an agent if thedevice 10 is filled with the agent by the user prior to use.

[0069] Cap 18 is shown mounted at delivery end 4. Cap 18 can be frictionfit to the external surface 35 of delivery end 4. Alternatively, or inaddition, cap 18 can include a stem 18 a which is friction fit into thedistal end 1 of lumen 6. Distal end 1 of lumen 6 could alternativelyhave female threads (not shown) which can threadedly receive malethreads (not shown) which can be present on the exterior surface of stem18 a. Cap 18 can also include a tab 18 b which provides for easiergripping of cap 18 when removing from tube 3.

[0070] Cap 18, could optionally include texturing, such as knurls,ridges, etc., to facilitate removal. Markings, such as a raised arrow,can optionally be added to the cap 18 to indicate the direction tounscrew for removal to contribute to the ease of use of the device.

[0071] In FIG. 5, pushing member 11 has been distally advanced to aposition that would cause expulsion of a pharmacological agent fromchamber 20. In the optional illustrated embodiment, when pushing member11 is distally advanced, the distal tip 16 of piston 15 protrudes beyondthe distal end 4 of elongate tube 3. In addition, distal tip 16 can beconvex shaped or domed outwardly to further ensure complete expulsion ofan agent from chamber 20.

[0072]FIG. 6 is a close-up view of an optional embodiment of a proximalend 2 of delivery device 10. In the illustrated embodiment, platform 14of pushing member 11 forms a shoulder 25 at the junction with thepushing end 12 of pushing member 11. When pushing member 11 is distallyadvanced within lumen 6, shoulder 25 may affirmatively stop by abuttingagainst the operating end 5 of elongate tube 3 which may indicatecomplete delivery of a pharmacological agent from chamber 20 of device10.

[0073]FIG. 7 is a close-up of an optional embodiment of a distal end 1of delivery device 10. As illustrated, the distal end of chamber 20 oflumen 6 may include a converging taper 30. The external surface 31 ofpiston 15 may also have a converging taper 32 that may extend to distaltip 16. The corresponding converging tapers 30 and 32 may facilitatecomplete delivery of a pharmacological agent contained within chamber 20when pushing member 11 is advanced distally. Piston 15 also may includea sealing ring 33 such as circumferential flange 34 which may fit snuglyagainst lumen 6 to assure that a significant portion, preferably all, ofthe pharmacological agent is removed from lumen 6 as piston 15 isadvanced distally. Thus, lumen 6 may have at least two differentdiameters, a lumen diameter L_(D) and a delivery diameter D_(D). Atypical lumen diameter L_(D) may be about 5 to about 15 mm and a typicaldelivery diameter may be about 2 to about 10 mm. In an example of adelivery device 10 with a maximum chamber volume of about 1 ml, thelength of elongate tube 3 can be about 12-20 cm, L_(D) can be about 10mm and D_(D) can be about 6 mm.

[0074] The external surface 35 of distal end 1 of elongate tube 3 mayalso have a converging taper 36 to facilitate insertion of the distalend 1 of device 10 into the vagina. After expulsion of an agent fromchamber 20, converging taper 36 may also ensure that all of thedispensed agent remains at the site of delivery. For example, whendelivering an agent to the cervix, the vaginal wall surrounding thedistal end 1 can drape closely around the distal tip 1 to wipe off anyof the agent remaining on the tip as compared to applicators having asquare-ended (i.e., right cylinder) tip or square-ended tip with roundedcorners.

[0075] In use, the user can place the thumb and middle finger proximalto flanges 8 a and 8 b of handle arrangement 7 to hold device 10 at aselected location while the user's index finger is placed on platform 14to distally advance pushing member 11 such that distal tip 16 of piston15 expels the pharmacological agent from chamber 20 to deliver the agentto an intravaginal location, such as the mucosal surface of the cervix.

[0076]FIG. 8 is an exploded perspective view of the components of anoptional alternative embodiment of an intravaginal delivery device 100.As illustrated, delivery device 100 may include a proximal end 101, adistal end 102 and a longitudinal axis X-X passing therethrough.Elongate tube 103 may have a delivery end 104, an operating end 105 anda lumen 106 passing therethrough. A cap 108 can be slidably orthreadedly mounted to distal end 102 of device 100 as described abovefor cap 18 of device 10.

[0077] The operating end 105 of elongate tube 103 may include a handlearrangement 107 including tip 118 to facilitate handling of device 100during use. In the optional illustrated embodiment, lip 118 may extendcontinuously around the circumference of the operating end 105. However,it will be appreciated that lip 118 need not be continuous and, in otherembodiments, lip 118 can be omitted.

[0078] Pushing member 111 can be slidably received into lumen 106 andmay include a pushing end 113, driving end 114 and a shaft 115 extendingtherebetween. The pushing end 113 can include a platform 116 forplacement of a user's thumb or finger to distally advance pushing member111 during use. Platform 116 can have a concave surface 117 to betterconform to the tip of a user's finger or thumb. Piston 120 can befixedly mounted to driving end 114 of pushing member 111 or driving end114 can be removably nested into bore 122 a at end 122. Piston 120 mayinclude a distal tip 121. In some embodiments, distal tip 121 can beconvexed distally or domed outwardly to further ensure completeexpulsion of the agent.

[0079]FIG. 9 is a longitudinal cross-section view of device 100 showingchamber 130 for containing or receiving a predetermined amount of apharmacological agent when pushing member 111 is proximally retractedwithin lumen 106 of elongate tube 103. FIG. 10 illustrates that whenpushing member 111 is distally advanced, the distal tip 121 of piston120 may extend beyond the distal end 102 of elongate tube 103.

[0080]FIG. 11 is a close-up view of the distal end 102 of the view ofdevice 100 illustrating that chamber 130 may include a converging taper131 at the distal end 102 of lumen 106. The optional converging taper131 of chamber 130 may be configured to match with a correspondingconverging taper 132 in a distal portion of piston 120. The convergingsurfaces 131 and 132 may facilitate complete expulsion of apharmacological agent contained within chamber 130.

[0081] Piston 120 also can include a sealing ring 133 such ascircumferential flange 134 which may fit snugly against lumen 106 toensure complete expulsion of the agent as piston 120 is advanceddistally. The external surface 135 of the distal end 102 of elongatetube 103 may be tapered 136 for reasons discussed above.

[0082] As with device 10, in some optional embodiments, lumen 106 caninclude a stop 140 such as protuberance 141 which may protrude intolumen 106 to prevent proximal retraction of piston 120. Whether device100 is pre-filled with an agent or filled by the user at the time ofuse, the position of stop 140 may provide a fixed maximum volume ofchamber 130 to contain a predetermined amount of an agent.

[0083]FIG. 12 is a close-up view of an optional embodiment of a proximalend 101 of device 100 of FIG. 10 illustrating that when pushing member111 is fully advanced distally, platform 116 of pushing end 113 may berecessed within the operating end 105 of elongate tube 103. This featurereduces the likelihood that some or all of the pharmacological agentdispensed from chamber 130 will be aspirated back into the chamber 130after delivery by inadvertent proximal retraction of pushing member 111after the pharmacological agent has been expelled.

[0084] Also, in some optional embodiments, the operating end 105 ofelongate tube 103 and the pushing end 113 of pushing member 111 can beconstructed to provide audible and/or tactile feedback to the user whenexpulsion of the agent is complete. According to this optionalembodiment, the operating end 105 of lumen 106 can include a projectingsurface 145 such as ridge 146 at a location proximal to platform 116when pushing member 111 is fully advanced distally. Platform 116 may besized such that as platform 116 is pushed distally past ridge 146 aclick can be heard and the movement past ridge 146 creates a tactileclick to inform the user of complete expulsion of the agent. Ridge 146may also act to “lock” pushing member 111 in the distally advancedportion and may prevent proximal retraction of pushing member 111.

[0085] It will be appreciated that in addition to lumen diameter L_(D)and delivery diameter D_(D), lumen 106 also has a diameter P_(O) atoperating end 105. Lumen 106 thus may have a taper 150 extending betweendiameter P_(O) and L_(D). In an example of a delivery device 100 havinga maximum chamber volume of about 1 ml, the length of elongate tube 103is about 15 to about 17 cm, L_(D) is about 11-15 mm and D_(D) is about7-12 mm.

[0086] In an optional alternative embodiment, the region of elongatetube 103, shown as having parallel sides (see e.g., FIG. 9) extendingfrom the proximal end to the distal end, can alternatively have aconverging taper from the proximal end to distal end. This mayadvantageously provide for filling the delivery device with apharmacological agent from the proximal end of elongate tube rather thanthe distal end. That is, without a taper as just described, attemptingto push the piston into place distally along a non-tapered tube, afterloading the formulation could be hindered by air that can be trappedbetween the piston seal and wall of the lumen. By tapering the elongatelumen as described, a gap may be maintained between the piston and thewall that may allow for air to escape as the piston is advanceddistally. Such a taper could occur gradually over the length of theelongate tube, or there can be an abrupt taper near where the piston isto be placed for setting a predetermined volume at the distal end of theelongate tube.

[0087]FIG. 13 illustrates another optional embodiment of the operatingend of an elongate tube suitable for an intravaginal delivery device 10,100 according to the invention. According to this embodiment, theoperating end 201 of elongate tube 200 may include a configuration whichprovides an indicator 203 of the orientation of device 200 aroundlongitudinal axis X-X. Thus, in the embodiment of FIG. 13, opposingsides 204 and 205 are linear giving the operating end an ovalcross-sectional configuration. In this embodiment, lip 206 may extendaround the perimeter of the operating end 201. It will be appreciated,however, that the lip may be completely absent or discontinuous aroundthe perimeter.

[0088]FIG. 14 illustrates another optional embodiment of the operatingend of an elongate tube 300 suitable for an intravaginal delivery deviceaccording to the invention. In this embodiment, the operating end 301 ofelongate tube 300 may include a configuration which also provides anindicator 303 for the orientation of device 300 around longitudinal axisX-X. Operating end 301 may include corners 304 a-304 d. The walls 305a-305 d of operating end 301 between corners 304 a-304 d form aconverging taper moving from operating end diameter P_(O) to lumendiameter L_(D). In the illustrated embodiment, the proximal aspect ofeach of walls 305 a-305 d may include a concave void 306 a-306 dextending distally into the surface of the walls 305 a-305 d,respectively. In addition, the platform 350 of the pushing member (notvisible) may have a distally concave surface 351 and four corners 352a-352 d configured to mate with the corners 304 a-304 d of walls 305a-305 d. A lip or flanges (not shown in this embodiment) may or may notbe present around the proximal edge of the operating end 301 asdescribed for device 10 and 110.

[0089] The intravaginal delivery device may provide for accuratedelivery of a volume of an agent that is less than the volumes typicallyused for other vaginal medications. Many vaginal applicators aredesigned to deliver about 5 ml of an agent and the application is notlocalized but rather it is delivered to the vaginal cavity in general.

[0090] In optional embodiments, such as that shown in FIG. 15, theapplicator 10 may be pre-filled with a product P to eliminate thepossibility of incorrect filling of the applicator. However, if thedevice is to be filled at the time of use, structure such as stops inthe device, may set a maximum volume that can help to eliminate thechance of exceeding a predetermined dosage.

[0091] Any of the above-mentioned applicators may have a lengthsufficient to allow the distal end of the applicator to be located at,or very close to, the cervix while a portion of the applicator passesthrough the vagina and proximal end is positioned outside the vagina.The length of the applicator may be configured to assure delivery of anIRM compound to the uppermost end of the vaginal cavity while theproximal end is outside the vagina. For example, the length of theapplicator may be sufficient to accommodate anatomical variability amongwomen, so that treatment of women with longer vaginal cavities will notbe compromised.

[0092] In use, the intravaginal delivery device could be held at theproximal end between the thumb and middle finger and the platform of thepushing member depressed (i.e., advanced distally) with the index fingerto deliver the agent.

[0093] In optional embodiments, the pushing member may be pre-positionedwithin the lumen of the elongate tube, ready for use. If the deliverydevice is to be filled prior to use, the distal end of the elongate tubecan include female threads to fit with male threads of a medicamentsource, such as an aluminum tube, to provide a threaded seal whiletransferring the medicament from the source to the chamber of thedelivery device.

[0094] The dispensers can be packaged in an overwrap pouch that providesfor asepsis as well as a moisture barrier. The overwrap pouch can bemade from any material suitable for protecting the pharmacological agentsuch as foils or foil laminates (e.g., a metal and plastic layer). Insome embodiments, the overwrap can protect against moisture loss fromthe formulation or oxidation of the formulation.

[0095] The applicator device could be part of a system or component usedin a method involving additional parts or components. In one optionalembodiment, the systems and methods include an immune response modifier(IRM) compound to treat or prevent conditions associated with a mucosalsurface. For example, the IRM compound could be in a formulation whichcan be applied to the mucosal surface of the cervix to treat cervicalconditions including cervical dysplasias such as cervicalintraepithelial neoplasia.

[0096] In some optional embodiments, the certain formulations may beused for application of an IRM compound to a mucosal surface. In someoptional embodiments, the formulations can enhance therapeuticefficiency of the IRM by facilitating mucosal permeation or increasingthe duration of contact of the IRM with the mucosal surface. Thepharmaceutical formulation may contain a preservative system thatrenders the formulations suitable for packaging in multiple-usecontainers.

[0097] IRM Compounds

[0098] As noted above, many of the imidazoquinoline amine,imidazopyridine amine, 6,7-fused cycloalkylimidazopyridine amine,1,2-bridged imidazoquinoline amine, thiazolo- and oxazolo-quinolinaminesand pyridinamines, imidazonaphthyridine andtetrahydroimidazonaphthyridine amine IRM compounds of the presentinvention have demonstrated significant immunomodulating activity. Someoptional immune response modifier compounds of the invention include1H-imidazo[4,5-c]quinolin-4-amines defined by one of Formulas I-V below:

[0099] wherein

[0100] R₁₁ is selected from the group consisting of alkyl of one to tencarbon atoms, hydroxyalkyl of one to six carbon atoms, acyloxyalkylwherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms orbenzoyloxy, and the alkyl moiety contains one to six carbon atoms,benzyl, (phenyl)ethyl and phenyl, said benzyl, (phenyl)ethyl or phenylsubstituent being optionally substituted on the benzene ring by one ortwo moieties independently selected from the group consisting of alkylof one to four carbon atoms, alkoxy of one to four carbon atoms andhalogen, with the proviso that if said benzene ring is substituted bytwo of said moieties, then said moieties together contain no more thansix carbon atoms;

[0101] R₂₁ is selected from the group consisting of hydrogen, alkyl ofone to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl,(phenyl)ethyl or phenyl substituent being optionally substituted on thebenzene ring by one or two moieties independently selected from thegroup consisting of alkyl of one to four carbon atoms, alkoxy of one tofour carbon atoms and halogen, with the proviso that when the benzenering is substituted by two of said moieties, then the moieties togethercontain no more than six carbon atoms; and

[0102] each R₁ is independently selected from the group consisting ofalkoxy of one to four carbon atoms, halogen, and alkyl of one to fourcarbon atoms, and n is an integer from 0 to 2, with the proviso that ifn is 2, then said R₁ groups together contain no more than six carbonatoms;

[0103] wherein

[0104] R₁₂ is selected from the group consisting of straight chain orbranched chain alkenyl containing two to ten carbon atoms andsubstituted straight chain or branched chain alkenyl containing two toten carbon atoms, wherein the substituent is selected from the groupconsisting of straight chain or branched chain alkyl containing one tofour carbon atoms and cycloalkyl containing three to six carbon atoms;and cycloalkyl containing three to six carbon atoms substituted bystraight chain or branched chain alkyl containing one to four carbonatoms; and

[0105] R₂₂ is selected from the group consisting of hydrogen, straightchain or branched alkyl containing one to eight carbon atoms, benzyl,(phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenylsubstituent being optionally substituted on the benzene ring by one ortwo moieties independently selected from the group consisting ofstraight chain or branched chain alkyl containing one to four carbonatoms, straight chain or branched chain alkoxy containing one to fourcarbon atoms, and halogen, with the proviso that when the benzene ringis substituted by two such moieties, then the moieties together containno more than six carbon atoms; and

[0106] each R₂ is independently selected from the group consisting ofstraight chain or branched chain alkoxy containing one to four carbonatoms, halogen, and straight chain or branched chain alkyl containingone to four carbon atoms, and n is an integer from zero to 2, with theproviso that if n is 2, then said R₂ groups together contain no morethan six carbon atoms;

[0107] wherein

[0108] R₂₃ is selected from the group consisting of hydrogen, straightchain or branched chain alkyl of one to eight carbon atoms, benzyl,(phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenylsubstituent being optionally substituted on the benzene ring by one ortwo moieties independently selected from the group consisting ofstraight chain or branched chain alkyl of one to four carbon atoms,straight chain or branched chain alkoxy of one to four carbon atoms, andhalogen, with the proviso that when the benzene ring is substituted bytwo such moieties, then the moieties together contain no more than sixcarbon atoms; and

[0109] each R₃ is independently selected from the group consisting ofstraight chain or branched chain alkoxy of one to four carbon atoms,halogen, and straight chain or branched chain alkyl of one to fourcarbon atoms, and n is an integer from zero to 2, with the proviso thatif n is 2, then said R₃ groups together contain no more than six carbonatoms;

[0110] wherein

[0111] R₁₄ is —CHR_(x)R_(y) wherein R_(y) is hydrogen or a carbon-carbonbond, with the proviso that when R_(y) is hydrogen R_(x) is alkoxy ofone to four carbon atoms, hydroxyalkoxy of one to four carbon atoms,1-alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkylwherein the alkoxy moiety contains one to four carbon atoms and thealkyl moiety contains one to four carbon atoms, 2-, 3-, or 4-pyridyl,and with the further proviso that when R_(y) is a carbon-carbon bondR_(y) and R_(x) together form a tetrahydrofuranyl group optionallysubstituted with one or more substituents independently selected fromthe group consisting of hydroxy and hydroxyalkyl of one to four carbonatoms;

[0112] R₂₄ is selected from the group consisting of hydrogen, alkyl ofone to four carbon atoms, phenyl, and substituted phenyl wherein thesubstituent is selected from the group consisting of alkyl of one tofour carbon atoms, alkoxy of one to four carbon atoms, and halogen; and

[0113] R₄ is selected from the group consisting of hydrogen, straightchain or branched chain alkoxy containing one to four carbon atoms,halogen, and straight chain or branched chain alkyl containing one tofour carbon atoms;

[0114] wherein

[0115] R₁₅ is selected from the group consisting of: hydrogen; straightchain or branched chain alkyl containing one to ten carbon atoms andsubstituted straight chain or branched chain alkyl containing one to tencarbon atoms, wherein the substituent is selected from the groupconsisting of cycloalkyl containing three to six carbon atoms andcycloalkyl containing three to six carbon atoms substituted by straightchain or branched chain alkyl containing one to four carbon atoms;straight chain or branched chain alkenyl containing two to ten carbonatoms and substituted straight chain or branched chain alkenylcontaining two to ten carbon atoms, wherein the substituent is selectedfrom the group consisting of cycloalkyl containing three to six carbonatoms and cycloalkyl containing three to six carbon atoms substituted bystraight chain or branched chain alkyl containing one to four carbonatoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein thealkoxy moiety contains one to four carbon atoms and the alkyl moietycontains one to six carbon atoms; acyloxyalkyl wherein the acyloxymoiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and thealkyl moiety contains one to six carbon atoms; benzyl; (phenyl)ethyl;and phenyl; said benzyl, (phenyl)ethyl or phenyl substituent beingoptionally substituted on the benzene ring by one or two moietiesindependently selected from the group consisting of alkyl of one to fourcarbon atoms, alkoxy of one to four carbon atoms, and halogen, with theproviso that when said benzene ring is substituted by two of saidmoieties, then the moieties together contain no more than six carbonatoms;

[0116] R₂₅ is

[0117] wherein

[0118] R_(S) and R_(T) are independently selected from the groupconsisting of hydrogen, alkyl of one to four carbon atoms, phenyl, andsubstituted phenyl wherein the substituent is selected from the groupconsisting of alkyl of one to four carbon atoms, alkoxy of one to fourcarbon atoms, and halogen;

[0119] X is selected from the group consisting of alkoxy containing oneto four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains oneto four carbon atoms and the alkyl moiety contains one to four carbonatoms, hydroxyalkyl of one to four carbon atoms, haloalkyl of one tofour carbon atoms, alkylamido wherein the alkyl group contains one tofour carbon atoms, amino, substituted amino wherein the substituent isalkyl or hydroxyalkyl of one to four carbon atoms, azido, chloro,hydroxy, 1-morpholino, 1-pyrrolidino, alkylthio of one to four carbonatoms; and

[0120] R₅ is selected from the group consisting of hydrogen, straightchain or branched chain alkoxy containing one to four carbon atoms,halogen, and straight chain or branched chain alkyl containing one tofour carbon atoms;

[0121] or a pharmaceutically acceptable salt of any of the foregoing.

[0122] Preferred 6,7 fused cycloalkylimidazopyridine amine IRM compoundsare defined by Formula VI below:

[0123] wherein m is 1, 2, or 3;

[0124] R₁₆ is selected from the group consisting of hydrogen; cyclicalkyl of three, four, or five carbon atoms; straight chain or branchedchain alkyl containing one to ten carbon atoms and substituted straightchain or branched chain alkyl containing one to ten carbon atoms,wherein the substituent is selected from the group consisting ofcycloalkyl containing three to six carbon atoms and cycloalkylcontaining three to six carbon atoms substituted by straight chain orbranched chain alkyl containing one to four carbon atoms; fluoro- orchloroalkyl containing from one to ten carbon atoms and one or morefluorine or chlorine atoms; straight chain or branched chain alkenylcontaining two to ten carbon atoms and substituted straight chain orbranched chain alkenyl containing two to ten carbon atoms, wherein thesubstituent is selected from the group consisting of cycloalkylcontaining three to six carbon atoms and cycloalkyl containing three tosix carbon atoms substituted by straight chain or branched chain alkylcontaining one to four carbon atoms; hydroxyalkyl of one to six carbonatoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbonatoms and the alkyl moiety contains one to six carbon atoms;acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to fourcarbon atoms or benzoyloxy, and the alkyl moiety contains one to sixcarbon atoms, with the proviso that any such alkyl, substituted alkyl,alkenyl, substituted alkenyl, hydroxyalkyl, alkoxyalkyl, or acyloxyalkylgroup does not have a fully carbon substituted carbon atom bondeddirectly to the nitrogen atom; benzyl; (phenyl)ethyl; and phenyl; saidbenzyl, (phenyl)ethyl or phenyl substituent being optionally substitutedon the benzene ring by one or two moieties independently selected fromthe group consisting of alkyl of one to four carbon atoms, alkoxy of oneto four carbon atoms, and halogen, with the proviso that when saidbenzene ring is substituted by two of said moieties, then the moietiestogether contain no more than six carbon atoms;

and —CHR_(x)R_(y)

[0125] wherein

[0126] R_(y) is hydrogen or a carbon-carbon bond, with the proviso thatwhen R_(y) is hydrogen R_(x) is alkoxy of one to four carbon atoms,hydroxyalkoxy of one to four carbon atoms, 1-alkynyl of two to tencarbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moietycontains one to four carbon atoms and the alkyl moiety contains one tofour carbon atoms, 2-, 3-, or 4-pyridyl, and with the further provisothat when R_(y) is a carbon-carbon bond R_(y) and R_(x) together form atetrahydrofuranyl group optionally substituted with one or moresubstituents independently selected from the group consisting of hydroxyand hydroxyalkyl of one to four carbon atoms,

[0127] R₂₆ is selected from the group consisting of hydrogen, straightchain or branched chain alkyl containing one to eight carbon atoms,straight chain or branched chain hydroxyalkyl containing one to sixcarbon atoms, morpholinoalkyl, benzyl, (phenyl)ethyl and phenyl, thebenzyl, (phenyl)ethyl or phenyl substituent being optionally substitutedon the benzene ring by a moiety selected from the group consisting ofmethyl, methoxy, and halogen; and

[0128] —C(R_(S))(R_(T))(X) wherein R_(S) and R_(T) are independentlyselected from the group consisting of hydrogen, alkyl of one to fourcarbon atoms, phenyl, and substituted phenyl wherein the substituent isselected from the group consisting of alkyl of one to four carbon atoms,alkoxy of one to four carbon atoms, and halogen;

[0129] X is selected from the group consisting of alkoxy containing oneto four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains oneto four carbon atoms and the alkyl moiety contains one to four carbonatoms, haloalkyl of one to four carbon atoms, alkylamido wherein thealkyl group contains one to four carbon atoms, amino, substituted aminowherein the substituent is alkyl or hydroxyalkyl of one to four carbonatoms, azido, alkylthio of one to four carbon atoms, and morpholinoalkylwherein the alkyl moiety contains one to four carbon atoms, and

[0130] R₆ is selected from the group consisting of hydrogen, fluoro,chloro, straight chain or branched chain alkyl containing one to fourcarbon atoms, and straight chain or branched chain fluoro- orchloroalkyl containing one to four carbon atoms and at least onefluorine or chlorine atom;

[0131] and pharmaceutically acceptable salts thereof.

[0132] Preferred imidazopyridine amine IRM compounds are defined byFormula VII below:

[0133] wherein

[0134] R₁₇ is selected from the group consisting of hydrogen; —CH₂R_(W)wherein R_(W) is selected from the group consisting of straight chain,branched chain, or cyclic alkyl containing one to ten carbon atoms,straight chain or branched chain alkenyl containing two to ten carbonatoms, straight chain or branched chain hydroxyalkyl containing one tosix carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one tofour carbon atoms and the alkyl moiety contains one to six carbon atoms,and phenylethyl; and —CH═CR_(Z)R_(Z) wherein each R_(Z) is independentlystraight chain, branched chain, or cyclic alkyl of one to six carbonatoms;

[0135] R₂₇ is selected from the group consisting of hydrogen, straightchain or branched chain alkyl containing one to eight carbon atoms,straight chain or branched chain hydroxyalkyl containing one to sixcarbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to fourcarbon atoms and the alkyl moiety contains one to six carbon atoms,benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenylsubstituent being optionally substituted on the benzene ring by a moietyselected from the group consisting of methyl, methoxy, and halogen; andmorpholinoalkyl wherein the alkyl moiety contains one to four carbonatoms;

[0136] R₆₇ and R₇₇ are independently selected from the group consistingof hydrogen and alkyl of one to five carbon atoms, with the proviso thatR₆₇ and R₇₇ taken together contain no more than six carbon atoms, andwith the further proviso that when R₇₇ is hydrogen then R₆₇ is otherthan hydrogen and R₂₇ is other than hydrogen or morpholinoalkyl, andwith the further proviso that when R₆₇ is hydrogen then R₇₇ and R₂₇ areother than hydrogen;

[0137] and pharmaceutically acceptable salts thereof.

[0138] Preferred 1,2-bridged imidazoquinoline amine IRM compounds aredefined by Formula VIII below:

[0139] wherein

[0140] Z is selected from the group consisting of:

[0141] —(CH₂)_(p)— wherein p is 1 to 4;

[0142] —(CH₂)_(a)—C(R_(D)R_(E))(CH₂)b—, wherein a and b are integers anda+b is 0 to 3, R_(D) is hydrogen or alkyl of one to four carbon atoms,and R_(E) is selected from the group consisting of alkyl of one to fourcarbon atoms, hydroxy, —OR_(F) wherein R_(F) is alkyl of one to fourcarbon atoms, and —NR_(G)R′_(G) wherein R_(G) and R′_(G) areindependently hydrogen or alkyl of one to four carbon atoms; and

[0143] —(CH₂)_(a)—(Y)—(CH₂)_(b)— wherein a and b are integers and a+b is0 to 3, and Y is O, S, or —NR_(J)— wherein R_(J) is hydrogen or alkyl ofone to four carbon atoms;

[0144] and wherein q is 0 or 1 and R₈ is selected from the groupconsisting of alkyl of one to four carbon atoms, alkoxy of one to fourcarbon atoms, and halogen,

[0145] and pharmaceutically acceptable salts thereof.

[0146] Suitable thiazolo- and oxazolo-quinolinamine and pyridinaminecompounds include compounds of Formula IX:

[0147] wherein:

[0148] R₁₉ is selected from the group consisting of oxygen, sulfur andselenium;

[0149] R₂₉ is selected from the group consisting of

[0150] -hydrogen;

[0151] -alkyl;

[0152] -alkyl-OH;

[0153] -haloalkyl;

[0154] -alkenyl;

[0155] -alkyl-X-alkyl;

[0156] -alkyl-X-alkenyl;

[0157] -alkenyl-X-alkyl;

[0158] -alkenyl-X-alkenyl;

[0159] -alkyl-N(R₅₉)₂;

[0160] -alkyl-N₃;

[0161] -alkyl-O—C(O)—N(R₅₉)₂;

[0162] -heterocyclyl;

[0163] -alkyl-X-heterocyclyl;

[0164] -alkenyl-X-heterocyclyl;

[0165] -aryl;

[0166] -alkyl-X-aryl;

[0167] -alkenyl-X-aryl;

[0168] -heteroaryl;

[0169] -alkyl-X-heteroaryl; and

[0170] -alkenyl-X-heteroaryl;

[0171] R₃₉ and R₄₉ are each independently:

[0172] -hydrogen;

[0173] -X-alkyl;

[0174] -halo;

[0175] -haloalkyl;

[0176] —N(R₅₉)₂;

[0177] or when taken together, R₃₉ and R₄₉ form a fused aromatic,heteroaromatic, cycloalkyl or heterocyclic ring;

[0178] X is selected from the group consisting of —O—, —S—, —NR₅₉—,—C(O)—,—C(O)O—, —OC(O)—, and a bond; and

[0179] each R₅₉ is independently H or C₁₋₈alkyl;

[0180] Suitable imidazonaphthyridine and tetrahydroimidazomaphthyridineIRM compounds are those of Formulae X and XI below:

[0181] wherein

[0182] A is ═N—CR═CR—CR═; ═CR—N═CR—CR═; ═CR—CR═N—CR═; or ═CR—CR═CR—N═;

[0183] R₁₁₀ is selected from the group consisting of:

[0184] -hydrogen;

[0185] —C₁₋₂₀alkyl or C₂₋₂₀alkenyl that is unsubstituted or substitutedby one or more substituents selected from the group consisting of:

[0186] -aryl;

[0187] -heteroaryl;

[0188] -heterocyclyl;

[0189] —O—C₁₋₂₀alkyl,

[0190] —O—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0191] —O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0192] —O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0193] —C₁₋₂₀alkoxycarbonyl;

[0194] —S(O)₀₋₂—C₁₋₂₀alkyl;

[0195] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0196] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0197] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0198] —N(R₃₁₀)₂;

[0199] —N₃;

[0200] oxo;

[0201] -halogen;

[0202] —NO₂;

[0203] —OH; and

[0204] —SH; and

[0205] —C₁₋₂₀alkyl-NR₃₁₀—Q—X—R₄₁₀ or —C₂₋₂₀alkenyl-NR₃₁₀—Q—X—R₄₁₀wherein Q is —CO— or —SO₂—; X is a bond, —O— or —NR₃₁₀— and R₄₁₀ isaryl; heteroaryl; heterocyclyl; or —C₁₋₂₀alkyl or

[0206] C₂₋₂₀alkenyl that is unsubstituted or substituted by one or moresubstituents selected from the group consisting of:

[0207] -aryl;

[0208] -heteroaryl;

[0209] -heterocyclyl;

[0210] —O—C₁₋₂₀alkyl,

[0211] —O—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0212] —O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0213] —O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0214] —C₁₋₂₀alkoxycarbonyl;

[0215] —S(O)₀₋₂—C₁₋₂₀alkyl;

[0216] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0217] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0218] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0219] —N(R₃₁₀)₂;

[0220] —NR₃₁₀—CO—O—C₁₋₂₀alkyl;

[0221] —N₃;

[0222] oxo;

[0223] -halogen;

[0224] —NO₂;

[0225] —OH; and

[0226] —SH; or R₄₁₀ is

[0227] wherein Y is —N— or —CR—;

[0228] R₂₁₀ is selected from the group consisting of:

[0229] -hydrogen;

[0230] —C₁₋₁₀alkyl;

[0231] —C₂₋₁₀alkenyl;

[0232] -aryl;

[0233] —C₁₋₁₀alkyl-O—C₁₋₁₀-alkyl;

[0234] —C₁₋₁₀alkyl-O—C₂₋₁₀alkenyl; and

[0235] —C₁₋₁₀alkyl or C₂₋₁₀alkenyl substituted by one or moresubstituents selected from the group consisting of:

[0236] —OH;

[0237] -halogen;

[0238] —N(R₃₁₀)₂;

[0239] —CO—N(R₃₁₀)₂;

[0240] —CO—C₁₋₁₀alkyl;

[0241] —N₃;

[0242] -aryl;

[0243] -heteroaryl;

[0244] -heterocyclyl;

[0245] —CO-aryl; and

[0246] —CO-heteroaryl;

[0247] each R₃₁₀ is independently selected from the group consisting ofhydrogen and C₁₋₁₀alkyl; and

[0248] each R is independently selected from the group consisting ofhydrogen,

[0249] C₁₋₁₀alkyl, C₁₋₁₀alkoxy, halogen and trifluoromethyl,

[0250] or a pharmaceutically acceptable salt thereof.

[0251] wherein

[0252] B is —NR—C(R)₂—C(R)₂—C(R)₂—; —C(R)₂—NR—C(R)₂—C(R)₂—;

[0253] —C(R)₂—C(R)₂—NR—C(R)₂— or —C(R)₂—C(R)₂—C(R)₂—NR—;

[0254] R₁₁₁ is selected from the group consisting of:

[0255] -hydrogen;

[0256] —C₁₋₂₀alkyl or C₂₋₂₀alkenyl that is unsubstituted or substitutedby one or more substituents selected from the group consisting of:

[0257] -aryl;

[0258] -heteroaryl;

[0259] -heterocyclyl;

[0260] —O—C₁₋₂₀alkyl;

[0261] —O—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0262] —O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0263] —O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0264] —C₁₋₂₀alkoxycarbonyl;

[0265] —S(O)₀₋₂—C₁₋₂₀alkyl;

[0266] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0267] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0268] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0269] —N(R₃₁₁)₂;

[0270] —N₃;

[0271] oxo;

[0272] -halogen;

[0273] —NO₂;

[0274] —OH; and

[0275] —SH; and

[0276] —C₁₋₂₀alkyl-NR₃₁₁—Q—X—R₄₁₁ or —C₂₋₂₀alkenyl-NR₃₁₁—Q—X—R₄₁₁wherein Q is —CO— or —SO₂—; X is a bond, —O— or —NR₃₁₁— and R₄₁₁ isaryl; heteroaryl; heterocyclyl; or —C₁₋₂₀alkyl or

[0277] C₂₋₂₀alkenyl that is unsubstituted or substituted by one or moresubstituents selected from the group consisting of:

[0278] -aryl;

[0279] -heteroaryl;

[0280] -heterocyclyl;

[0281] —O—C₁₋₂₀alkyl,

[0282] —O—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0283] —O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0284] —O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0285] —C₁₋₂₀alkoxycarbonyl;

[0286] —S(O)₀₋₂—C₁₋₂₀alkyl;

[0287] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0288] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0289] —S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0290] —N(R₃₁₁)₂;

[0291] —NR₃₁₁—CO—O—C₁₋₂₀alkyl;

[0292] —N₃;

[0293] oxo;

[0294] -halogen;

[0295] —NO₂;

[0296] —OH; and

[0297] —SH; or R₄₁₁ is

[0298] wherein Y is —N— or —CR—;

[0299] R₂₁₁ is selected from the group consisting of:

[0300] -hydrogen;

[0301] —C₁₋₁₀alkyl;

[0302] —C₂₋₁₀alkenyl;

[0303] -aryl

[0304] —C₁₋₁₀alkyl-O—C₁₋₁₀-alkyl;

[0305] —C₁₋₁₀alkyl-O—C₂₋₁₀alkenyl; and

[0306] —C₁₋₁₀alkyl or C₂₋₁₀alkenyl substituted by one or moresubstituents selected from the group consisting of:

[0307] —OH;

[0308] -halogen;

[0309] —N(R₃₁₁)₂;

[0310] —CO—N(R₃₁₁)₂;

[0311] —CO—C₁₋₁₀alkyl;

[0312] —N₃;

[0313] -aryl;

[0314] -heteroaryl;

[0315] -heterocyclyl;

[0316] —CO-aryl; and

[0317] —CO-heteroaryl;

[0318] each R₃₁₁ is independently selected from the group consisting ofhydrogen and C₁₋₁₀alkyl; and

[0319] each R is independently selected from the group consisting ofhydrogen, C₁₋₁₀alkyl,

[0320] C₁₋₁₀alkoxy, halogen and trifluoromethyl, and pharmaceuticallyacceptable salts thereof.

[0321] The compounds recited above are disclosed in the patents andapplications noted above in the background, all of which areincorporated herein by reference.

[0322] The substituents R₁₁-R₁₁₁ above are generally designated“1-substituents” herein. The preferred 1-substituents are alkylcontaining one to six carbon atoms and hydroxyalkyl containing one tosix carbon atoms. Optionally, the 1-substituent is 2-methylpropyl or2-hydroxy-2-methylpropyl.

[0323] The substituents R₂₁-R₂₁₁ above are generally designated“2-substituents” herein. Optional 2-substituents are hydrogen, alkyl ofone to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety containsone to four carbon atoms and the alkyl moiety contains one to fourcarbon atoms, and hydroxyalkyl of one to four carbon atoms. Optionally,the 2-substituent is hydrogen, methyl, butyl, propyl hydroxymethyl,ethoxymethyl or methoxyethyl.

[0324] In instances where n can be zero, one, or two, n is preferablyzero or one.

[0325] IRM Pharmaceutical Formulations

[0326] The amount of an IRM compound that will be therapeuticallyeffective in a specific situation will depend on such things as theactivity of the particular compound, the mode of administration, theparticular formulation and the condition being treated. As such, it isnot practical to identify specific administration amounts herein;however, those skilled in the art will be able to determine appropriatetherapeutically effective amounts based on the guidance provided herein,information available in the art pertaining to these compounds, androutine testing.

[0327] The pharmaceutical formulations described below can be used fortopical administration of an IRM. Many of the formulations provided areparticularly advantageous for topical administration to a mucosalsurface. In some embodiments, the formulations can affect thepharmacokinetics of the IRM such that reduced concentrations of the IRMprovide similar pharmacodynamic affects as that of other formulationshaving a greater IRM concentration.

[0328] Generally, a pharmaceutical formulation of the invention includesan IRM, a fatty acid, a preservative system and an optional viscosityenhancing agent such as a carbomer. The IRMs can be prepared usingmethods previously described in the patents listed in the backgroundsection above as well as U.S. Pat. Nos. 4,988,815; 5,367,076; 5,175,296;5,395,937; and 5,741,908, the disclosures which are incorporated hereinby reference. Unless otherwise specified, all percentages are weightpercentages based on the total composition weight.

[0329] The amount of an IRM present in a pharmaceutical formulation ofthe invention will be an amount effective to treat a targeted condition,to prevent recurrence of the condition, or to promote immunity againstthe condition. The amount of IRM is preferably about 0.1% to about 9% byweight based on the total formulation weight. Optionally, the IRM amountdoes not exceed about 5% by weight and most preferably is about 0.1 toabout 3% by weight for mucosal surface applications.

[0330] Typically, a pharmaceutical formulation of the invention is anoil in water emulsion. The oil component of the formulation includes anIRM and a fatty acid. The fatty acid is present in the formulation in anamount sufficient to solubilize the IRM. This is generally about 2% toabout 45%, typically about 10% to about 30%, and preferably about 15% toabout 18% based on the total weight of the formulation. Fatty acids suchas isostearic acid are suitable for the formulations. Alternatively, theIRM can be solubilized in linear chain carboxylic acids of six to eightcarbon atoms.

[0331] A pharmaceutical formulation of the invention can also include anemulsifier such as a non-ionic surfactant. Suitable surfactants include,for example, polysorbate 60, sorbitan monostearate, polyglyceryl-4oleate, polyoxyethylene(4)lauryl ether, etc. For some formulations,surfactants such as Poloxamers (e.g., Pluronic F68 available from BASF,Ludwigschafen, Germany) and sorbitan trioleate (e.g., Span 85 availablefrom Sigma Chemical Co., St. Louis, Mo.), alone or in combination, arepreferred. The non-ionic surfactant is typically present in an amount ofabout 0.5% to about 10% of total formulation weight. In preferredembodiments, the total emulsifier content does not exceed about 5% oftotal formulation weight, and is more preferably about 3.5% of totalformulation weight.

[0332] A formulation of the invention can also include a viscosityenhancing agent such as a carbomer, preferably having mucoadhesiveproperties. The carbomer can be present in an amount of about 0.1% toabout 8%, preferably about 0.5% to about 4%, more preferably about 0.5to about 3%, and most preferably about 1.0% of total formulation weight.Suitable carbomers include polyacrylic acids such as Carbopol 934P,Carbopol 971P, Carbopol 940 and Carbopol 974P available from B. F.Goodrich. A preferred carbomer is Carbopol 974P.

[0333] In some optional embodiments, the formulation can also include achelating agent. The chelating agent functions to chelate metal ions. Ifpresent, unchelated metal ions can suppress gel formation by suppressingionization which facilitates gel formation in a carbomer containingformulation. An optional chelating agent is disodiumethylenediaminetetraacetate (EDTA) in a concentration of about 0.0001 toabout 0.5%, typically about 0.0005 to about 0.1% per total formulationweight.

[0334] A preservative such as methylparaben, sorbic acid, propyleneglycol, etc. can also be added. In one optional embodiment,methylparaben and sorbic acid are each provided at concentrations ofabout 0.05% to about 0.3%, preferably about 0.15% of total formulationweight and propylene glycol is present in amounts up to about 30%,preferably about 5%. It was discovered that this combination ofpreservatives advantageously meets the Preservation Effectiveness Test(PET), 1997 European Pharmacopeia, Test 5.1.3 Efficacy AntimicrobialPreservation—Topical Preparations—A Criteria. This renders theformulation suitable for use in a multi-dose dispenser without adverselyaffecting the stability of the formulation. The methylparaben and sorbicacid can be solubilized in propylene glycol prior to adding to theformulation.

[0335] The remainder of the pharmaceutical formulation can be comprisedof water to provide a formulation that can be washed away from themucosal surface by normal physiological clearing mechanisms.

[0336] In addition to providing mucoadhesive properties to theformulation, the carbomer also increases viscosity by forming astabilizing gel. Many factors, such as the amount of oil phase, the drugload, and the amount of carbomer used will affect the pH at whichgelation occurs. In some formulations, the presence of metal ions andsurfactants increases the pH at which the carbomer will form a gel.Thus, in the absence of a chelating agent, or in the presence ofincreased surfactant levels, the pH at which the carbomer will gel canbe increased. Thus it may be necessary to add an organic or inorganicbase or other substance to facilitate gel formation. Suitable inorganicbases include, for example, KOH, NaOH, etc. The pH for a pharmaceuticalformulation of the invention is typically about pH 3.0 to about pH 7.0,preferably about pH 4.0 to about pH 6.0.

[0337] Mucosal Surface Applications

[0338] According to the invention, the compositions can be appliedtopically, particularly to non-cornified epithelial surfaces such asmucosal surfaces. Mucosal surfaces include mucosal membranes such asbuccal, gingival, nasal, tracheal, bronchial, gastrointestinal, rectal,urethral, ureteral, vaginal, cervical, uterine, etc. Depending on theIRM concentration, formulation composition, and mucosal surface, thetherapeutic affect of the IRM may extend only to the superficial layersof the mucosal surface or to tissues deep to the surface.

[0339] In one embodiment, the disclosed IRMs can be topically applied tothe vaginal or supravaginal region of the cervix for treatment ofdysplastic conditions such as cervical intraepithelial neoplasia. Insome embodiments, the above described formulations are particularlyadvantageous for cervical application of an IRM for a period of timesufficient to obtain a desired therapeutic effect without undesiredsystemic absorption of the IRM.

[0340] Cervical Intraepithelial Neoplasia (CIN)

[0341] Approximately 16,000 new cases of invasive cancer of the cervixare diagnosed each year in the U.S. despite extensive screening of womento detect predictive cellular changes. There are also about 3,000 deathsdue to cervical cancer in the U.S. alone and this is usually secondaryto not detecting the primary cancerous lesion in a timely manner.

[0342] The Papanicoulaou Test (Pap smear) is the screening test whichhas been accepted since the 1950s as the method to detect abnormal cellsof the cervix, including inflammation and dysplasia, which includescervical cancer. This screening test has been widely adopted inindustrialized countries and has had a profound impact on mortalityassociated with cervical cancers. An abnormal Pap smear prompts closeobservation for disease progression with the potential for thetherapeutic interventions of destruction or excision of cancerous orpre-cancerous tissues. These excisional treatments are expensive,uncomfortable and associated with failure rates which range from 2 to23% and with higher failure rates reported for the more advancedlesions. Failure rates have recently been documented to approximate 10%following laser treatment.

[0343] The etiologic agent for cervical cancer was originally thought tobe the herpes virus. However, there was a gradual shift from this focuson herpes virus to the human papillomavirus (HPV) when it was shown thatthe cytopathic effects of HPV in experimental systems very closelymimicked what was seen in human disease. Improved experimental methodsover the recent past have allowed the characterization of a fullspectrum of HPV subtypes, which has resulted in the conclusion that thehigh risk HPV types (e.g., HPV 16, 18, and less frequently 31, 33, 35,45) are very likely the exclusive initiating factor (i.e., oncogenicagent) for cervical dysplasia and subsequent cancers. The mechanism ofHPV transformation of the normal cell to a dysplastic cell is associatedwith the HPV encoded oncoproteins (E6 and E7) from the high riskgenotypes binding the cell's tumor suppressor gene products p53 and Rbresulting in disruption of the cell cycle control mechanism in which p53and Rb play an important role. In addition, the application of thesemolecular methods has resulted in the epidemilogic observation that HPVis isolated from approximately 93% of cervical tumors, which has furtherstrengthened the generally accepted conclusion that HPV infection is themost important initiating agent for cervical cancer.

[0344] Exposure to HPV is common in sexually active women, but it doesnot invariably lead to dysplasia or cancer in most of the exposed women.Infected women who harbor persistent viral DNA have about five times thechance of persistent dysplasia compared to women who are able toeradicate the virus. The importance of cell-mediated immune (CMI)response to HPV infection is illustrated by the observation that theantibody mediated immune response is not effective in eliminatingestablished infections as is demonstrated by the fact that patients withinvasive cervical dancer often exhibit high antibody levels against theviral E6 and E7 proteins. This particular antibody response probablyreflects extensive antigen exposure in the face of increasing tumorburden. In contrast to the apparently inconsequential effect of thehumoral immune response, the cell-mediated immune response (Th-1-TypeResponse) appears to be effective in controlling tumor progression.Regression of intraepithelial lesions is accompanied by a cellularinfiltrate consisting of CD4⁺ T-CELLS, CD8⁺ T-CELLS, natural killercells (NK) and macrophages. This inflammatory infiltrate was usuallyassociated with tumor regression which is in contrast to women who lackthe ability to mount this inflammatory response and who experiencedisease progression. In addition, patients with a defect incell-mediated immunity have increased cervical cancer rates, whereasthose with defects in the production of antibody do not exhibit the samesusceptibility.

[0345] In one optional embodiment, the inventors foresee the topicalapplication of IRMs for the non-invasive treatment of cervicalconditions including cervical intraepithelial neoplasia (CIN).

[0346] Intravaginal Applicators for an IRM

[0347] To obtain a beneficial therapeutic or prophylactic effect for acervical condition, intravaginal application of a herein disclosed IRMis preferred. The IRM can be applied via a dosing formulation ordispenser which ensures contact of the IRM with the mucosal surface ofthe cervix for a period of time sufficient to provide the desiredtherapeutic effect. Any of the dispensers (i.e., applicators) describedherein and/or shown in the drawings could be used to apply the IRM.

[0348] In addition to the applicators already described, an IRM can beformulated as a suppository and administered intravaginally using asuppository applicator. A suitable suppository applicator includes knowncardboard tube applicators for dispensing medications to the vaginalcavity. Formulations according to the invention can also be administeredusing a barrel type applicator, such as those described herein and/orshown in the drawings. An example of a suitable barrel type applicatorcan be found in U.S. Pat. No. 5,282,789, the disclosure of which isincorporated herein by reference.

[0349] In optional embodiment, an IRM can be administered directly tothe cervical mucosa. In one such embodiment, the IRM can be topicallyapplied to the cervical mucosa by using a direct cervical applicator, aspreviously described or using a cervical cap. One example of a suitablecervical cap is found in U.S. Pat. No. 4,858,624, the disclosure ofwhich is incorporated herein by reference. Suitable IRM formulations fordirect cervical applications are disclosed above and in the Examplesbelow. In general, an IRM formulated pursuant to any of formulations A-Jin the Examples below can be placed into the concave region of thecervical cap which is then applied directly over the cervix. Theseformulations might also be applied with other types of applicatordevices including those shown in the drawings and described herein.Optionally, the IRM is formulated to include a viscosity agent, such asa carbomer, to enhance the residence time of the IRM on the cervix.

[0350] The following Examples are provided to further describe IRMformulations and methods according to the invention. The examples,however, are not intended to limit the formulations and methods.

EXAMPLES Example 1 Evaluation of the Safety, Pharmacokinetics (PK) andPharmacodynamics (PD) OF1-(2-Methylpropyl)-1H-imadazo[4,5-C]quinolin-4-amine (imiquimod) Appliedto the Cervix.

[0351] Methods

[0352] This was a single dose, randomized, double-blind, placebocontrolled dose escalation study which evaluated five doses ofimiquimod. 50, 100, 150, 200 and 250 mg of imiquimod in a creamformulation were applied to the cervix for eight hours. The ingredientsof the formulation of the imiquimod cream used for this study(Formulation A) is presented in Table I below. Each dose group wascomposed of 8 subjects (6 active and 2 placebo), with two subjectstreated as dose leaders, and the remaining six subjects were treatedafter an acceptable response by the dose leaders. Safety was assessed byadverse events (AE's), laboratory tests, and colposcopy withphotodocumentation of the cervix at pre-dose and 24 hours post-dose, and48 hours post-dose if required. Systemic exposure (PK) was determined bymeasuring imiquimod and metabolites through 48 hours post-dose and thePD response was determined by serum analysis for the cytokines: tumornecrosis factor-α (TNF-α), interferon-α (IFN-α), interleukin-1 receptoragonist (IL-1RA), interleukin-6 (IL-6), neopterin (NPT) and 2′5′oligoadenlyate synthetase (2′5′ AS) during dosing and selected timesduring the 48 hours post-dose. Statistical tests to evaluate AE's anddemographics, laboratory tests, vital signs and ECG's were Fisher'sExact, Wilcoxon Rank-Sum and Kruskall Wallis Tests respectively.Cytokine changes between dose groups were compared using WilcoxonRank-Sum and changes from baseline were evaluated using Spearman RankCorrelation.

[0353] Results

[0354] Thirty-nine generally healthy, surgically sterilized, 18-50year-old females within 25% of ideal body weight were included in thestudy. All women had normal baseline colposcopy results with normal andborderline dyskariosis on cervical histology. AE's were reported in eachof the 39 subjects with mild temperature elevation the most common event(92%). There were no differences among groups with respect to subjectswho experienced one or more events, or in AE's attributed as possibly orprobably related to drug. (Two serious AE's occurred which wereintercurrent events associated with a fractured ankle and its surgicalrepair.) There were statistically significant changes in some laboratoryparameters and pulse rates that were not considered clinicallysignificant. There were no differences in ECG's or physical exams.Pelvic and colposcopic examinations revealed few reactions with 2 of 6receiving 250 mg experiencing cervical changes of minor small vesiclesor smaller ulcer. These reactions resolved within 48 hours. Noquantifiable (>5 ng/ml) serum levels of imiquimod were detected.Significant changes from baseline were seen in IFN and IL-6 in the 250mg group and in NPT. 2′5′ AS and IL-1RA in the 150 mg, 200 mg, and 250mg groups.

[0355] The study showed that single doses of imiquimod up to 250 mgapplied to the cervix for 8 hours in healthy volunteers is safe withminimal systemic exposure. Cervical application of a dose ≧150 mgincreases the systemic concentration of certain cytokines. TABLE 1Components Formulation A (% w/w) Imiquimod 5.0 Isostearic Acid 25.0Benzyl Alcohol 2.0 Cetyl Alcohol 2.2 Stearyl Alcohol 3.1 WhitePetrolatum 3.0 Polysorbate 60 3.4 Sorbitan Monostearate 0.6 Glycerin 2.0Methyl Paraben 0.2 Propyl Paraben 0.02 Water 52.98 Xanthan Gum 0.5 PH5.1 Viscosity (cps) 0.33 × 10⁵

Example 2 Preparation of Pharmaceutical Formulation B

[0356] This example describes a novel formulation for a vaginalapplication, that is a stable formulation, with a high viscosity, andwell preserved to pass the EP preservative effectiveness test (PET)criteria. The w/w % of ingredients of this formulation (Formulation B)are shown in Table 2 below.

[0357] Imiquimod was dissolved in isostearic acid with Span 85. PluronicF68, EDTA, Carbopol 974P, propylene glycol, sorbic acid, andmethylparaben were dissolved in water. After emulsification to form anoil-in-water emulsion, sodium hydroxide was added to achieve a pH ofabout 5.2. The pH range for this formulation can be about 4.8 to 6.0.TABLE 2 Components Formulation B (% w/w) Imiquimod 5 Isostearic acid 28Pluronic F68 2.98 Purified water 43.78 Carbopol 974P 1.7 Disodium EDTA0.05 Propylene glycol 15 Sorbic acid 0.15 Methylparaben 0.15 Span 852.02 5N NaOH 1.17 PH 5.1 Viscosity (cps) 6.4 × 10⁵

Example 3 Preparation of Pharmaceutical Formulations C-F

[0358] Pharmaceutical Formulations C-F were prepared with the componentsrecited below in Table 3. The method for preparing Formulations C-F wasthe same as that disclosed for preparing Formulation B in Example 2.TABLE 3 Formu- Formu- Formu- Formu- lation C lation D lation E lation FComponents (% w/w) (% w/w) (% w/w) (% w/w) Imiquimod 1.0 1.0 3.0 3.0Isostearic acid 5.6 28.0 16.8 28.0 Pluronic F68 1.79 1.79 1.79 1.79Purified water 69.05 48.30 56.25 46.75 Carbopol 974P 2.8 2.10 2.5 1.80Disodium 0.05 0.05 0.05 0.05 EDTA PG* 15.0 15.0 15.0 15.0 Sorbic acid0.15 0.15 0.15 0.15 Methylparaben 0.15 0.15 0.15 0.15 Span 85 1.21 1.211.21 1.21 5N NaOH 3.2 2.26 3.1 2.1 pH 5.1 5.2 5.2 5.3 Viscosity (cps)5.8 × 10⁵ 8.8 × 10⁵ 11.0 × 10⁵ 10.0 × 10⁵

Example 4 Imiquimod Transport Across Hairless Mouse Skin from TwoFormulations A AND B, Both at 5% W/W Imiquimod.

[0359]FIG. 16 is a graph of the results of imiquimod penetration studiesof Formulations A and B, of Examples 1 and 2, using hairless mouse skinaccording to the procedure described in U.S. Pat. No. 5,238,944, theentire disclosure of which is incorporated herein by reference.

[0360] In brief, hairless mouse skin was removed from female hairlessmice that were 5 to 7 weeks old (available from Charles River). The skinwas maintained on ice until used. The mouse skin was mounted on adiffusion cell of the type shown in U.S. Pat. No. 5,238,944. The mouseskin was mounted with the epidermal side up between upper and lowerportions of the cell which are held together by means of ball jointclamp.

[0361] The portion of the cell below the mounted skin was completelyfilled with 0.1 N HCl receptor fluid such that the receptor fluidcontacted the skin. The receptor fluid was stirred using a magnetic stirbar and a magnetic stirrer.

[0362] Approximately 100^(±)5 mg formulation to be tested was applied tothe epidermal (upper) side of the skin to cover in an even layer onlythe area of skin that would be in contact with the receptor fluid whenthe skin was mounted in the diffusion cell. The formulations wereapplied to the skin prior to the time the receptor fluid was added tothe cell below the skin.

[0363] The cell was then placed in a constant temperature (31° C.)chamber. To maintain constant temperature, the chamber utilized a heatexchanger coupled to a constant temperature bath, with a fan tocirculate air. The receptor fluid was stirred by means of a magneticstirring bar throughout the experiment to ensure a uniform sample and areduced diffusion barrier layer on the dermal side of the skin. Atspecified time intervals (1, 2, 4, 6, 8, 12 and 24 hours), the entirevolume of receptor fluid was removed and immediately replaced with freshreceptor fluid. The withdrawn receptor fluid was analyzed for imiquimodcontent by conventional high pressure chromatography as follows:

[0364] Detector: UV at 258 nm; Mobile Phase: 25/75 acetonitrile/watercontaining 1% triethylamine, 0.2% 1-octane sulfonate with the pHadjusted to 2.0 with H₃PO₄; Stationary Phase: C8 Zorbax RX-C8 5μ; FlowRate: 2 ml/min; Run Time: approximately 10 minutes.

[0365] Cumulative amount of penetration was plotted versus time toobtain the steady state rate.

Example 5 Imiquimod Transport Across Nude Skin from Formulations C-F at1% W/W and 3% W/W Imiquimod with Varied Concentrations of IsostearicAcid (ISA)

[0366] Table 4 below provides the imiquimod concentration, isostearicacid concentration, viscosity, pH and steady state rate (μg/hour) ofFormulations C-F across nude mouse skin.

[0367] The results are graphed in FIG. 17. The procedure used to studyskin penetration was the same as that disclosed in Example 4. TABLE 4IRM ISA Steady Concentration Concentration Viscosity State RateFormulation (% w/w) (% w/w) (×10⁻⁵ cps) (μg/hr) C 1%  5.6% 5.8 18.1 D 1%  28% 8.8 26.1 E 3% 16.8% 11 39.9 F 3%   28% 10 71.5

Example 6 Pharmacokinetics Comparison of Imiquimod in Rats after SingleDose Vaginal Application of Formulation A and Formulation B

[0368] Serum imiquimod concentration versus time profiles were comparedin ovariectomized rats after single intravaginal doses of Formulation Aor Formulation B. The two 5% w/w formulations were dosed to provide adose level of 35 mg/kg. After dosing, each rat was collared to preventremoval of the formulation by licking. After about six hours, the vaginawas lavaged and the collars removed. Blood samples were collected atpre-dose and at 0.5, 1, 2, 3, 4 and 24 hours post-dose. Due to thehigher viscosity of Formulation B, intravaginal administration to therats was considerably easier and retention of Formulation B was superiorto Formulation A.

[0369] Serum was analyzed by HPLC for imiquimod. Mean serum imiquimodconcentrations versus time are depicted in FIG. 18. The time to achievemaximum serum concentrations of imiquimod (T_(max)) was similar (1 hr)for both formulations. However, the maximum imiquimod concentration(C_(max)) for Formulation B was approximately 1.6 times greater than forFormulation A and the respective area under the curve versus time (AUC)was 3.3 times greater (FIGS. 19A and 19B). Based upon these data, therate and extent of absorption of imiquimod was greater from FormulationB than from Formulation A.

Example 7 Preparation of Pharmaceutical Formulation G

[0370] The w/w % of the ingredients for Formulation G are shown in Table5.

[0371] An oil phase was prepared as follows. Imiquimod (20.0 g) wasslowly added with stirring to isostearic acid (3000 g). The mixture wasstirred and heated, as necessary, up to 55° C. to facilitate dissolutionof the imiquimod. After dissolution was complete the heat was turnedoff. Sorbitan trioleate (200 g) was added and thoroughly mixed. Carbomer974 was slowly added with mixing. The mixing was continued until thecarbomer was uniformly dispersed in the oil phase. The oil phase wasthen allowed to cool to a temperature of less than 30° C.

[0372] An aqueous phase was prepared as follows. Sorbic acid (30.0 g)and methylparaben (40.0 g) were added with stirring to propylene glycol(1000 g). The resulting mixture was stirred and heated gently (<45° C.)until a solution was obtained. The heat source was removed. Polaxamer188 (500 g) was added to the solution. The resulting mixture was stirreduntil the polaxamer was thoroughly wet. The resulting slurry was thenadded to a solution of edetate disodium (10.0 g) in purified water(13950 g). The resulting mixture was stirred until a clear solution wasobtained.

[0373] A sodium hydroxide solution was prepared by dissolving sodiumhydroxide pellets (50 g) in purified water (1000 g).

[0374] The oil phase was added to the aqueous phase and then the sodiumhydroxide solution was added. The resulting mixture was mixed for aminimum of 30 minutes until a smooth and shiny cream was obtained. ThepH was determined and adjusted, if necessary, to 5.6-5.8 with sodiumhydroxide solution.

Example 8 Preparation of Pharmaceutical Formulations H-J

[0375] Pharmaceutical formulations H-J were prepared using the method ofExample 7. The w/w % of the ingredients in the formulations is shown inTable 5 below. TABLE 5 Formulation G H I J Component (% w/w) (% w/w) (%w/w) (% w/w) Isostearic Acid 15.00  15.00  15.00  18.00  (874) Imiquimod0.10 0.50 1.50 3.00 Sorbitan Trioleate 1.00 1.00 1.00 1.00 PropyleneGlycol 5.00 5.00 5.00 5.00 Sorbic Acid 0.15 0.15 0.15 0.15 Methylparaben0.20 0.20 0.20 0.20 Purified Water 75.00  74.60  73.60  69.10  EdetateDisodium 0.05 0.05 0.05 0.05 Polaxamer 188 2.50 2.50 2.50 2.50 Carbomer974 1.00 1.00 1.00 1.00 Sodium Hydroxide qs qs qs Os Total % w/w 100   100    100    100   

[0376] Accordingly, from the foregoing discussion, it will appreciatedthat the imidazoquinoline amines, imidazopyridine amines, 6,7-fusedcycloalkylimidazopyridine amines, and 1,2-bridged imidazoquinolineamines of the present invention can be beneficial for treating mucosalassociated conditions including cervical dysplasias. In addition, thedisclosed pharmaceutical formulations can be particularly advantageousfor topical application of an IRM to a mucosal surface.

[0377] From the foregoing detailed description and examples, it will beevident that modifications and variations can be made in the compounds,formulations, devices, systems, and methods disclosed herein. Otherembodiments will be apparent to those skilled in the art. It is intendedthat the specification and examples be considered as exemplary only.

What is claimed is:
 1. A system for treating a condition associated witha mucosal surface, the system comprising: an immune response modifier(IRM) compound chosen from imidazoquinoline amines, imidazopyridineamines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridgedimidazoquinoline amines, and pharmaceutically acceptable salts thereof;and an applicator device for applying to the mucosal surface the IRMcompound.
 2. The system of claim 1, wherein the IRM compound is1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine.
 3. The system ofclaim 1, wherein the IRM compound is4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol.4. The system of claim 1, wherein the system further comprises apharmaceutical formulation comprising: the IRM compound; at least onefatty acid; and a preservative system comprising propylene glycol. 5.The system of claim 1, wherein the applicator device is pre-filled witha therapeutically effective amount of the IRM compound.
 6. The system ofclaim 1, wherein the IRM compound is contained in a container separatefrom the device.
 7. The system of claim 1, further comprising measuringmarks on the applicator device for assisting a user in determining theamount of the IRM compound in the applicator device.
 8. The system ofclaim 1, wherein the condition associated with the mucosal surface iscervical dysplasia.
 9. The system of claim 1, wherein the mucosalsurface is on a cervix.
 10. The system of claim 9, wherein the mucosalsurface is on the vaginal part of the cervix.
 11. The system of claim10, wherein the condition associated with the mucosal surface iscervical intraepithelial neoplasia.
 12. The system of claim 1, whereinthe applicator device comprises: a hollow tube comprising a distaldelivery end and a proximal end; and a piston slidably received withinthe tube.
 13. The system of claim 12, further comprising a memberconfigured to cause movement of the piston toward the distal end. 14.The system of claim 13, wherein the device is configured to limitretraction movement of the member toward the proximal end when thepiston is located adjacent to the distal end.
 15. The system of claim13, wherein the piston is removably coupled to the member.
 16. Thesystem of claim 13, wherein the member is slidably received in thehollow tube.
 17. The system of claim 12, further comprising a stoplimiting retraction movement of the piston toward the proximal end. 18.The system of claim 12, wherein the piston comprises a portion extendingfrom the distal end when the piston is positioned at its farthestlocation away from the proximal end.
 19. The system of claim 12, whereinthe distal end is tapered on its outer surface.
 20. The system of claim13, wherein the member has a length shorter than the distance betweenthe proximal end and the piston when the piston is positioned at itsfurthest location away from the proximal end.
 21. A system for treatinga condition associated with a mucosal surface, the system comprising: animmune response modifier (IRM) compound chosen from imidazoquinolineamines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridineamines, imidazonaphthyridine amines, oxazoloquinoline amines,thiazoloquinoline amines, 1,2-bridged imidazoquinoline amines, andpharmaceutically acceptable salts thereof; and an applicator device forapplying to the mucosal surface the IRM compound.
 22. The system ofclaim 21, wherein the IRM compound is1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine.
 23. The system ofclaim 21, wherein the IRM compound is4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol.24. The system of claim 21, wherein the IRM compound is2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine.
 25. The system of claim21, wherein the system further comprises a pharmaceutical formulationcomprising: the IRM compound; at least one fatty acid; and apreservative system comprising propylene glycol.
 26. The system of claim21, wherein the applicator device is pre-filled with a therapeuticallyeffective amount of the IRM compound.
 27. The system of claim 21,wherein the IRM compound is contained in a container separate from thedevice.
 28. The system of claim 21, further comprising measuring markson the applicator device for assisting a user in determining the amountof the IRM compound in the applicator device.
 29. The system of claim21, wherein the condition associated with the mucosal surface iscervical dysplasia.
 30. The system of claim 21, wherein the mucosalsurface is on a cervix.
 31. The system of claim 30, wherein the mucosalsurface is on the vaginal part of the cervix.
 32. The system of claim31, wherein the condition associated with the mucosal surface iscervical intraepithelial neoplasia.
 33. The system of claim 21, whereinthe applicator device comprises: a hollow tube comprising a distaldelivery end and a proximal end; and a piston slidably received withinthe tube.
 34. The system of claim 33, further comprising a memberconfigured to cause movement of the piston toward the distal end. 35.The system of claim 34, wherein the device is configured to limitretraction movement of the member toward the proximal end when thepiston is located adjacent to the distal end.
 36. The system of claim34, wherein the piston is removably coupled to the member.
 37. Thesystem of claim 34, wherein the member is slidably received in thehollow tube.
 38. The system of claim 33, further comprising a stoplimiting retraction movement of the piston toward the proximal end. 39.The system of claim 33, wherein the piston comprises a portion extendingfrom the distal end when the piston is positioned at its farthestlocation away from the proximal end.
 40. The system of claim 33, whereinthe distal end is tapered on its outer surface.
 41. The system of claim34, wherein the member has a length shorter than the distance betweenthe proximal end and the piston when the piston is positioned at itsfurthest location away from the proximal end.
 42. A method for treatinga condition associated with a mucosal surface, the method comprising:providing an immune response modifier (IRM) compound chosen fromimidazoquinoline amines, imidazopyridine amines, 6,7-fusedcycloalkylimidazopyridine amines, imidazonaphthyridine amines,oxazoloquinoline amines, thiazoloquinoline amines, 1,2-bridgedimidazoquinoline amines, and pharmaceutically acceptable salts thereof;providing an applicator device for applying to the mucosal surface theIRM compound; and applying the IRM compound to the mucosal surface withthe applicator device.
 43. The method of claim 42, wherein the IRMcompound is 1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine. 44.The method of claim 42, wherein the IRM compound is4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol.45. The method of claim 42, wherein the IRM compound is2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine.
 46. The method of claim42, wherein the applicator device is pre-filled with a therapeuticallyeffective amount of the IRM compound.
 47. The method of claim 42,further comprising filling the applicator device with the IRM compound,wherein the IRM compound is contained in a container separate from thedevice.
 48. The method of claim 47, wherein the applicator devicecomprises measuring marks and wherein the method further comprises usingthe marks to determine the amount of the IRM compound in the applicatordevice.
 49. The method of claim 42, further comprising: inserting theapplicator device into the vagina; positioning a distal end of theapplicator device adjacent to the mucosal surface; and applying the IRMcompound to the mucosal surface, wherein the mucosal surface is on acervix.
 50. The method of claim 42, further comprising positioning adistal end of the applicator device adjacent to the vaginal part of thecervix, and applying the IRM compound to the mucosal surface, whereinthe mucosal surface is on the vaginal part of the cervix.
 51. The methodof claim 42, wherein the condition associated with the mucosal surfaceis cervical intraepithelial neoplasia.
 52. The method of claim 42,wherein the applicator device comprises a hollow tube comprising adistal delivery end and a proximal end, and a piston slidably receivedwithin the tube and wherein the method comprises moving the piston inthe tube to cause dispensing of the IRM compound via the distal end. 53.The method of claim 52, wherein the applicator device further comprisesa member configured to cause movement of the piston toward the distalend, and wherein the method comprises moving the member to cause themovement of the piston.
 54. The method of claim 53, further comprisinglimiting retraction movement of the member toward the proximal end whenthe piston is located adjacent to the distal end.
 55. The method ofclaim 53, wherein the piston is removably coupled to the member andwherein the method further comprises uncoupling the member from thepiston.
 56. The method of claim 53, further comprising sliding themember in the hollow tube.
 57. The method of claim 52, furthercomprising limiting retraction movement of the piston toward theproximal end.
 58. The method of claim 52, further comprising extending aportion of the piston from the distal end when the piston is positionedat its farthest location away from the proximal end.